Besides motor symptoms, many individuals with Parkinson’s disease develop cognitive impairment perhaps due to co-existing α-synuclein and Alzheimer’s disease pathologies and impaired brain insulin signaling. Discovering biomarkers for cognitive impairment in Parkinson’s disease could help clarify the underlying pathogenic processes and improve Parkinson’s disease diagnosis and prognosis. This study used plasma samples from 271 participants: 103 Parkinson’s disease individuals with normal cognition, 121 Parkinson’s disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia), and 49 age and sex-matched Controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-synuclein was lower in Parkinson’s disease compared to Control individuals (p = 0.004) and in cognitively impaired Parkinson’s disease individuals compared to Parkinson’s disease with normal cognition (p < 0.001) and Control (p < 0.001) individuals. Amyloid-beta42 did not differ between groups. Phosphorylated Tau (T181) was higher in Parkinson’s disease than Control individuals (p = 0.003), and in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p < 0.001) and Controls (p < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson’s disease compared to Control individuals (p = 0.03), and in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p = 0.02) and Controls (p = 0.01), and also decreased with increasing motor symptom severity (p = 0.005); Serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p = 0.05). The ratio of α-synuclein to phosphorylated Tau181 was lower in Parkinson’s disease compared to Controls (p = 0.001), in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p < 0.001), and decreased with increasing motor symptom severity (p < 0.001). The ratio of insulin receptor substrate-1 phosphorylated Serine312 to insulin receptor substrate-1 phosphorylated Tyrosine was higher in Parkinson’s disease compared to Control individuals (p = 0.01), in cognitively impaired compared to cognitively normal Parkinson’s disease individuals (p = 0.02) and increased with increasing motor symptom severity (p = 0.003). α-synuclein, phosphorylated Tau181, and insulin receptor substrate-1 phosphorylated Tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and Tau pathologies and impaired insulin signaling underlie Parkinson’s disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson’s disease.

中文翻译：

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帕金森病认知障碍的细胞外囊泡生物标志物

除了运动症状外，许多帕金森病患者还会出现认知障碍，这可能是由于 α-突触核蛋白和阿尔茨海默病病理学共存以及大脑胰岛素信号传导受损所致。发现帕金森病认知障碍的生物标志物有助于阐明潜在的致​​病过程并改善帕金森病的诊断和预后。这项研究使用了 271 名参与者的血浆样本：103 名认知正常的帕金森病患者、121 名患有认知障碍的帕金森病患者（81 名患有轻度认知障碍，40 名患有痴呆），以及 49 名年龄和性别匹配的对照。通过靶向 L1 细胞粘附分子来免疫捕获富含神经元来源的血浆细胞外囊泡，然后使用免疫测定对生物标志物进行定量。与对照个体相比，帕金森病患者的α-突触核蛋白较低（p = 0.004），与认知正常的帕金森病患者（p < 0.001）和对照个体（p < 0.001）相比，认知受损的帕金森病患者的α-突触核蛋白较低。淀粉样蛋白-β42 在各组之间没有差异。帕金森病患者的磷酸化 Tau (T181) 高于对照个体 (p = 0.003)，而认知障碍患者的磷酸化 Tau (T181) 高于认知正常的帕金森病个体 (p < 0.001) 和对照个体 (p < 0.001)。各组之间的总 tau 蛋白没有差异。与对照个体相比，帕金森病患者的酪氨酸磷酸化胰岛素受体底物-1 较低（p = 0.03），与认知正常的帕金森病个体（p = 0.02）和对照个体（p = 0.01）相比，认知障碍患者的酪氨酸磷酸化胰岛素受体底物-1 较低，并且也降低随着运动症状严重程度的增加（p = 0.005）；丝氨酸 312 磷酸化胰岛素受体底物 1 在各组之间没有差异。雷帕霉素的机械靶点在各组之间没有差异，而与认知正常的帕金森病个体相比，认知受损的雷帕霉素的磷酸化机械靶点趋于较低（p = 0.05）。与对照组相比，帕金森病患者的 α-突触核蛋白与磷酸化 Tau181 的比率较低（p = 0.001），与认知正常的帕金森病患者相比，认知受损的患者的 α-突触核蛋白与磷酸化 Tau181 的比率较低（p < 0.001），并且随着运动症状严重程度的增加而降低（p < 0.001）。 ；0.001）。与对照组相比，帕金森病患者的胰岛素受体底物 1 磷酸化丝氨酸 312 与胰岛素受体底物 1 磷酸化酪氨酸的比率较高 (p = 0.01)，与认知正常的帕金森病患者相比，认知障碍患者 (p = 0.02) 的比率更高随着运动症状严重程度的增加（p = 0.003）。α-突触核蛋白、磷酸化 Tau181 和胰岛素受体底物 1 磷酸化酪氨酸有助于组间的诊断分类。这些发现表明 α-突触核蛋白和 Tau 病理学以及胰岛素信号传导受损是帕金森病和认知障碍的基础。血浆神经元细胞外囊泡生物标志物可能有助于帕金森病的认知预后。